Dose synthesis card for use with automated biomarker production system

ABSTRACT

Microfluidic radiopharmaceutical production system and process for synthesizing per run approximately, but not less than, ten (10) unit doses of radiopharmaceutical biomarker for use in positron emission tomography (PET). A radioisotope from an accelerator or other radioisotope generator is introduced into a reaction vessel, along with organic and aqueous reagents, and the mixture heated to synthesize a solution of a pre-selected radiopharmaceutical. The solution is purified by passing through a combination of solid phase extraction purification components, trap and release components, and a filter. The synthesis process reduces waste and allows for production of biomarker radiopharmaceuticals on site and close to the location where the unit dose will be administered to the patient. On-site, as-needed production of radiopharmaceuticals in small doses reduces the time between synthesis of the radiopharmaceutical and administration of that radiopharmaceutical, minimizing loss of active isotopes through decay and allowing production of lesser amounts of radioisotopes overall.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation-in-part of U.S. patent applicationSer. No. 13/446,334, filed Apr. 13, 2012, which is acontinuation-in-part of U.S. patent application Ser. No. 12/565,544,filed Sep. 23, 2009, now U.S. Pat. No. 8,333,952, and acontinuation-in-part of U.S. patent application Ser. No. 12/565,552,filed Sep. 23, 2009. The contents of the foregoing applications areincorporated herein by reference.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention concerns a chemical apparatus and process forsynthesizing and purifying radiopharmaceuticals for use in positronemission tomography (PET). Specifically, the present invention relatesto a system for analyzing a liquid sample of PET biomarker.

2. Description of the Related Art

A biomarker is used to interrogate a biological system and can becreated by “tagging” or labeling certain molecules, includingbiomolecules, with a radioisotope. A biomarker that includes apositron-emitting radioisotope is required for positron-emissiontomography (PET), a noninvasive diagnostic imaging procedure that isused to assess perfusion or metabolic, biochemical and functionalactivity in various organ systems of the human body. Because PET is avery sensitive biochemical imaging technology and the early precursorsof disease are primarily biochemical in nature, PET can detect manydiseases before anatomical changes take place and often before medicalsymptoms become apparent. PET is similar to other nuclear medicinetechnologies in which a radiopharmaceutical is injected into a patientto assess metabolic activity in one or more regions of the body.However, PET provides information not available from traditional imagingtechnologies, such as magnetic resonance imaging (MRI), computedtomography (CT) and ultrasonography, which image the patient's anatomyrather than physiological images. Physiological activity provides a muchearlier detection measure for certain forms of disease, cancer inparticular, than do anatomical changes over time.

A positron-emitting radioisotope undergoes radioactive decay, wherebyits nucleus emits positrons. In human tissue, a positron inevitablytravels less than a few millimeters before interacting with an electron,converting the total mass of the positron and the electron into twophotons of energy. The photons are displaced at approximately 180degrees from each other, and can be detected simultaneously as“coincident” photons on opposite sides of the human body. The modern PETscanner detects one or both photons, and computer reconstruction ofacquired data permits a visual depiction of the distribution of theisotope, and therefore the tagged molecule, within the organ beingimaged.

Most clinically-important positron-emitting radioisotopes are producedin a cyclotron. Cyclotrons operate by accelerating electrically-chargedparticles along outward, quasi-spherical orbits to a predeterminedextraction energy generally on the order of millions of electron volts.The high-energy electrically-charged particles form a continuous beamthat travels along a predetermined path and bombards a target. When thebombarding particles interact in the target, a nuclear reaction occursat a sub-atomic level, resulting in the production of a radioisotope.The radioisotope is then combined chemically with other materials tosynthesize a radiochemical or radiopharmaceutical (hereinafter“radiopharmaceutical”) suitable for introduction into a human body. Thecyclotrons traditionally used to produce radioisotopes for use in PEThave been large machines requiring great commitments of physical spaceand radiation shielding. These requirements, along with considerationsof cost, made it unfeasible for individual hospitals and imaging centersto have facilities on site for the production of radiopharmaceuticalsfor use in PET.

Thus, in current standard practice, radiopharmaceuticals for use in PETare synthesized at centralized production facilities. Theradiopharmaceuticals then must be transported to hospitals and imagingcenters up to 200 miles away. Due to the relatively short half-lives ofthe handful of clinically important positron-emitting radioisotopes, itis expected that a large portion of the radioisotopes in a givenshipment will decay and cease to be useful during the transport phase.To ensure that a sufficiently large sample of active radiopharmaceuticalis present at the time of the application to a patient in a PETprocedure, a much larger amount of radiopharmaceutical must besynthesized before transport. This involves the production ofradioisotopes and synthesis of radiopharmaceuticals in quantities muchlarger than one (1) unit dose, with the expectation that many of theactive atoms will decay during transport.

The need to transport the radiopharmaceuticals from the productionfacility to the hospital or imaging center (hereinafter “site oftreatment”) also dictates the identity of the isotopes selected for PETprocedures. Currently, fluorine isotopes, and especially fluorine-18 (orF-18) enjoy the most widespread use. The F-18 radioisotope is commonlysynthesized into [¹⁸F]fluorodeoxyglucose, or [¹⁸F]FDG, for use in PET.F-18 is widely used mainly because its half-life, which is approximately110 minutes, allows for sufficient time to transport a useful amount.The current system of centralized production and distribution largelyprohibits the use of other potential radioisotopes. In particular,carbon-11 has been used for PET, but its relatively short half-life of20.5 minutes makes its use difficult if the radiopharmaceutical must betransported any appreciable distance. Similar considerations largelyrule out the use of nitrogen-13 (half-life: 10 minutes) and oxygen-15(half-life: 2.5 minutes).

As with any medical application involving the use of radioactivematerials, quality control is important in the synthesis and use of PETbiomarker radiopharmaceuticals, both to safeguard the patient and toensure the effectiveness of the administered radiopharmaceutical. Forexample, for the synthesis of [¹⁸F]FDG from mannose triflate, a numberof quality control tests exist. The final [¹⁸F]FDG product should be aclear, transparent solution, free of particulate impurities; therefore,it is important to test the color and clarity of the finalradiopharmaceutical solution. The final radiopharmaceutical solution isnormally filtered through a sterile filter before administration, and itis advisable to test the integrity of that filter after the synthesizedradiopharmaceutical solution has passed through it. The acidity of thefinal radiopharmaceutical solution must be within acceptable limits(broadly a pH between 4.5 and 7.5 for [¹⁸F]FDG, although this range maybe different depending upon the application and the radiopharmaceuticaltracer involved). The final radiopharmaceutical solution should betested for the presence and levels of volatile organics, such as ethanolor methyl cyanide, that may remain from synthesis process. Likewise, thesolution should be tested for the presence of crown ethers or otherreagents used in the synthesis process, as the presence of thesereagents in the final dose is problematic. Further, the radiochemicalpurity of the final solution should be tested to ensure that it issufficiently high for the solution to be useful. Other tests, such astests of radionuclide purity, tests for the presence of bacterialendotoxins, and tests of the sterility of the synthesis system, areknown in the art.

At present, most or all of these tests are performed on each batch ofradiopharmaceutical, which will contain several doses. The qualitycontrol tests are performed separately by human technicians, andcompleting all of the tests typically requires between 45 and 60minutes.

BRIEF SUMMARY OF THE INVENTION

In the present invention, a PET biomarker production system includes aradioisotope generator, a radiopharmaceutical production module, and aquality control module. PET biomarker production system is designed toproduce approximately ten (10) unit doses of a radiopharmaceuticalbiomarker very efficiently. The overall assembly includes a small,low-power cyclotron, particle accelerator or other radioisotopegenerator (hereinafter “accelerator”) for producing approximately ten(10) unit doses of a radioisotope. The system also includes amicrofluidic chemical production module. The chemical production moduleor CPM receives the unit dose of the radioisotope and reagents forsynthesizing the unit dose of a radiopharmaceutical.

The accelerator produces per run a maximum quantity of radioisotope thatis approximately equal to the quantity of radioisotope required by themicrofluidic chemical production module to synthesize ten doses ofbiomarker. Chemical synthesis using microreactors or microfluidic chips(or both) is significantly more efficient than chemical synthesis usingconventional (macroscale) technology. Percent yields are higher andreaction times are shorter, thereby significantly reducing the quantityof radioisotope required in synthesizing a unit dose ofradiopharmaceutical. Accordingly, because the accelerator is forproducing per run only such relatively small quantities of radioisotope,the maximum power of the beam generated by the accelerator isapproximately two to three orders of magnitude less than that of aconventional particle accelerator. As a direct result of this dramaticreduction in maximum beam power, the accelerator is significantlysmaller and lighter than a conventional particle accelerator, has lessstringent infrastructure requirements, and requires far lesselectricity. Additionally, many of the components of the small,low-power accelerator are less expensive than the comparable componentsof conventional accelerators. Therefore, it is feasible to use thelow-power accelerator and accompanying CPM within the grounds of thesite of treatment. Because radiopharmaceuticals need not be synthesizedat a central location and then transported to distant sites oftreatment, less radiopharmaceutical need be produced, and differentisotopes, such as carbon-11, may be used if desired.

If the accelerator and CPM are in the basement of the hospital or justacross the street from the imaging center, then radiopharmaceuticals forPET can be administered to patients almost immediately after synthesis.However, eliminating or significantly reducing the transportation phasedoes not eliminate the need to perform quality control tests on the CPMand the resultant radiopharmaceutical solution itself. Still, it isessential to reduce the time required to perform these quality controltests in order to take advantage of the shortened time between synthesisand administration. The traditional 45 to 60 minutes required forquality control tests on radiopharmaceuticals produced in macro scale isclearly inadequate. Further, since the accelerator and the CPM areproducing a radiopharmaceutical solution that is approximately just ten(10) unit doses, it is important that the quality control tests not usetoo much of the radiopharmaceutical solution; after some solution hasbeen sequestered for testing, enough radiopharmaceutical solution mustremain to make up an effective unit dose.

The sample card and quality control module allow operators to conductquality control tests in reduced time using micro-scale test samplesfrom the radiopharmaceutical solution. The sample card works inconjunction with the CPM to collect samples of radiopharmaceuticalsolution on the scale of up to 100 microliters per sample. The samplecard then interacts with the quality control module (or QCM) to feed thesamples into a number of test vessels, where the samples undergo anumber of automated diagnostic tests. Because the quality control testsare automated and run in parallel on small samples, the quality controltesting process may be completed in under 20 minutes. Further, under thetraditional system of macroscale radiopharmaceutical synthesis andquality control testing, a radiopharmaceutical solution would beproduced as a batch, and quality control tests would be performed on theentire batch, with each batch producing several doses ofradiopharmaceutical. Here, because the PET biomarker production systemproduces approximately one unit dose per run, at least some qualitycontrol tests may be performed on every dose, rather than on the batchas a whole.

In some embodiments of the present general inventive concept, adisposable microfluidic radiopharmaceutical synthesis card systemincludes at least one reaction vessel adapted to receive a radioisotopeand at least one reagent, said reaction vessel being in energy-transfercommunication with an energy source, whereby when said radioisotope andsaid at least one reagent are mixed in said reaction vessel and energyis provided to said reaction vessel from said energy source, aradiopharmaceutical solution is synthesized; at least one purificationcomponent used to purify said radiopharmaceutical solution; a filteradapted to sterilize said radiopharmaceutical solution; a sterile vesseladapted to receive sterile radiopharmaceutical solution following thepassage of said radiopharmaceutical solution through said purificationcolumn and said filter, said sterile vessel to hold multiple unit dosesof radiopharmaceutical; and a port in said vessel used to extract asample of said radiopharmaceutical for quality control testing; whereinsaid reaction vessel, said purification component, said port, and saidfilter are incorporated into a disposable card, said card beingdiscarded after one (1) run, and wherein said system is scaled toproduce per run multiple unit doses of radiopharmaceutical.

Some embodiments also include a sample card adapted to receive multiplealiquots of said purified radiopharmaceutical solution for testingfollowing said purified radiopharmaceutical solution's passage throughsaid purification column.

In some embodiments, any number of said at least one purificationcomponent is selected from the group consisting of trap and release, andsolid phase extraction.

In some embodiments, at least one of said reagents is located on thecard.

In some embodiments, the radioisotope is selected from the groupconsisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18,iodine-124, and gallium-68.

In some embodiments, the radiopharmaceutical is selected from the groupconsisting of [18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride,[18F] 3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole,[18F]flurocholine, [18F]Fallypride, [18F]Florbetaben, [18F]Florbetapir,[18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]FDOPA,[11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone,[11C]Carfentanil and [11C]Raclopride.

In some embodiments, a unique identifying barcode/RF id chip is used toidentify said radiopharmaceutical. In some embodiments, a uniqueidentifying barcode/RF id chip is used by an AutomatedRadiopharmaceutical Production and Quality Control System to identify aparticular radiopharmaceutical solution run.

In some embodiments, the vessel adapted to receive saidradiopharmaceutical solution includes a syringe.

In some embodiments, the vessel adapted to receive saidradiopharmaceutical solution includes a vial.

In some embodiments of the present general inventive concept, adisposable microfluidic radiopharmaceutical synthesis card encompassesat least one reaction vessel adapted to receive a radioisotope and atleast one reagent, said reaction vessel being in energy-transfercommunication with an energy source, whereby when said radioisotope andsaid at least one reagent are mixed in said reaction vessel and energyis provided to said reaction vessel from said energy source, aradiopharmaceutical solution is synthesized; at least one purificationcomponent used to purify said radiopharmaceutical solution; a port usedto extract a sample of said radiopharmaceutical solution for qualitycontrol testing; a filter adapted to sterilize said radiopharmaceuticalsolution; and a sterile dispensing device to receive sterileradiopharmaceutical solution following the passage of saidradiopharmaceutical solution through said purification column and saidfilter, said sterile vessel to hold multiple unit doses ofradiopharmaceutical.

In some embodiments, at least one of said at least one purificationcomponent is selected from the group consisting of trap and release, andsolid phase extraction.

In some embodiments, at least one of said reagents is located on thecard.

In some embodiments, said radioisotope is selected from the groupconsisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18,iodine-124, and gallium-68.

In some embodiments, said radiopharmaceutical is selected from the groupconsisting of [18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride,[18F] 3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole,[18F]flurocholine, [18F]Fallypride, [18F]Florbetaben, [18F]Florbetapir,[18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]FDOPA,[11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone,[11C]Carfentanil and [11C]Raclopride.

In some embodiments, a unique identifying barcode/RF id chip is used toidentify said radiopharmaceutical.

In some embodiments, said sterile dispensing device to receive saidradiopharmaceutical solution includes a syringe.

In some embodiments, wherein said sterile dispensing device to receivesaid radiopharmaceutical solution includes a vial.

In some embodiments of the present general inventive concept, a methodof preparing a radiopharmaceutical solution includes supplying aradioisotope to a reaction vessel located on a disposable card;supplying at least one reagent to said reaction vessel; applying energyto said reaction vessel to synthesize a radiopharmaceutical solutionfrom said radioisotope and said at least one reagent; passing theradiopharmaceutical solution through at least one purification componentlocated on said disposable card; extracting a sample of theradiopharmaceutical solution for quality control testing; passing theradiopharmaceutical solution through a filter located on said card; anddelivering the radiopharmaceutical solution to a sterile dispensingdevice located on said card.

In some embodiments, the extraction of a sample of theradiopharmaceutical solution for quality control testing takes placebefore passing the radiopharmaceutical solution through a filter locatedon said card.

In some embodiments, said method further comprises gamma-irradiation ofthe radiopharmaceutical solution.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The above-mentioned features of the invention will become more clearlyunderstood from the following detailed description of the invention readtogether with the drawings in which:

FIG. 1 is an schematic illustration of one embodiment of the overall PETbiomarker production system, including the accelerator, the chemicalproduction module (CPM), the dose synthesis card, the sample card, andthe quality control module (QCM);

FIG. 2 is another view of the embodiment shown in FIG. 1, showing thesample card interacting with the quality control module (QCM);

FIG. 3 is a flow diagram of one embodiment of the chemical productionmodule (CPM), the dose synthesis card, and the sample card;

FIG. 4 is a flow diagram of one embodiment of the sample cardinteracting with one embodiment of the quality control module (QCM);

FIG. 5 is a schematic illustration of an embodiment of the dosesynthesis card and the sample card;

FIG. 6 is a schematic illustration of an embodiment of the dosesynthesis card which only has a connection line to QC system and nosample card; and

FIG. 7 is a schematic illustration of a automated radiopharmaceuticalproduction system with automated QC which does not require a samplecard.

DETAILED DESCRIPTION OF THE INVENTION

A chemical production module and dose synthesis card for a PET biomarkerradiopharmaceutical production system are described more fullyhereinafter. This invention may, however, be embodied in many differentforms and should not be construed as limited to the embodiments setforth herein. Rather, these embodiments are provided to ensure that thisdisclosure is thorough and complete, and to ensure that it fully conveysthe scope of the invention to those skilled in the art.

The chemical production module, the dose synthesis card and the samplecard operate in conjunction with a complete PET biomarker productionsystem. As shown in FIG. 1, one embodiment of this PET biomarkerproduction system comprises an accelerator 10, which produces theradioisotopes; a chemical production module (or CPM) 20; a dosesynthesis card 30; a sample card 40; and a quality control module (orQCM) 50. Once the accelerator 10 has produced a radioisotope, theradioisotope travels via a radioisotope delivery tube 112 to the dosesynthesis card 30 attached to the CPM 20. The CPM 20 holds reagents andsolvents that are required during the radiopharmaceutical synthesisprocess. In the dose synthesis card 30, the radiopharmaceutical solutionis synthesized from the radioisotope and then purified for testing andadministration. Following synthesis and purification, a small percentageof the resultant radiopharmaceutical solution is diverted into thesample card 40, while the remainder flows into a dose vessel 200. FIG. 7shows an embodiment of the automatic production system with a QC systemthat does not require a sample card 51. As shown in FIG. 2, once samplesof the radiopharmaceutical solution have flowed into the sample card 40,an operator removes the sample card 40 from the CPM 20 and interfaces itwith the QCM 50, where a number of diagnostic instruments performautomated quality control tests on the samples.

FIGS. 3 and 4 present a more detailed overview of the complete synthesisand quality control testing processes for one embodiment of the presentinvention. In this embodiment, the radioisotope involved is flourine-18(F-18), produced from the bombardment in a cyclotron of heavy watercontaining the oxygen-18 isotope. However, the sample card and qualitycontrol module also work with radiopharmaceutical synthesis systemsusing other radioisotopes, including carbon-11, nitrogen-13, andoxygen-15.

As shown in FIG. 3, the radioisotope enters a reaction chamber orreaction vessel 110 from the radioisotope delivery tube 112. At thisstage, the radioisotope F-18 is still mixed with quantities of heavywater from the biomarker generator. Next, a first organic ingredient isintroduced to the reaction vessel 110 from a reagent storage compartment120 by an organic input pump 124. In some embodiments, the first organicingredient includes a solution of potassium complexed to1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane (commonlycalled Kryptofix 222™, hereinafter “kryptofix”) or a similar crownether. In many embodiments, the potassium-kryptofix complex or similarorganometallic complex is carried by acetonitrile as solvent. Thepotassium activates the F-18 fluoride radioisotope, while the kryptofixbinds the potassium atoms and inhibits the formation of apotassium-fluoride complex. Next, a gas input 142 fills the reactionvessel 110 with an inert gas such as dry nitrogen, the gas having beenstored in a storage area 140 within or near the CPM 20. Next, themixture in the reaction vessel 110 is heated by the nearby heat source114 to remove the residual heavy water by evaporating the azeotropicwater/acetonitrile mixture. A vacuum 150 helps to remove the vaporizedwater. Then, the organic input pump 124 adds a second organic ingredientfrom a second reagent storage compartment 122 to the mixture in thereaction vessel 110. In many embodiments, the second organic ingredientis mannose triflate in dry acetonitrile.

In some embodiments of the present general inventive concept, thereaction vessel 110 is in energy-transfer communication with an energysource, whereby when said radioisotope and said at least one reagent aremixed in said reaction vessel and energy is provided to said reactionvessel from said energy source, a radiopharmaceutical solution issynthesized. In various embodiments, the energy used to activate and/ordrive the reaction within the reaction vessel 110 includes heat,microwave radiation, IR radiation, UV radiation, or similar forms ofenergy. In some embodiments, the solution is heated at approximately 110degrees Celsius for approximately two minutes. The F-18 has bonds to themannose to form the immediate precursor for [¹⁸F]FDG, commonly18F-fluorodeoxyglucose tetraacetate (FTAG). Next, aqueous acid—in manyembodiments, aqueous hydrochloric acid—is introduced from a storagecompartment 130 through an aqueous input pump 132. The hydrochloric acidremoves the protective acetyl groups on the ¹⁸F-FTAG, leaving¹⁸F-fludeoxyglucose (i.e. [¹⁸F]FDG).

The [¹⁸F]FDG having been synthesized, it must be purified before testingand administration. The [¹⁸F]FDG in solution passes from the reactionvessel 110 through a solid phase extraction column 160. In someembodiments of the present invention, the solid phase extraction column160 comprises a length filled with an ion exchange resin, a lengthfilled with alumina, and a length filled with carbon-18. The [¹⁸F]FDGnext passes through a filter 170, which in many embodiments includes aMillipore filter with pores approximately 0.22 micrometers in diameter.

Once the radiopharmaceutical solution has passed through the filter 170,some of the solution is diverted into the sample card 40, which containsa number of sample vessels 402 a-e, which in some embodiments each holdapproximately 10 microliters of solution. The number of sample vesselswill vary according to the number of quality control tests to beperformed for that run, and the system is adapted to operate withdifferent sample cards containing varying numbers of sample vessels. Theremainder of the radiopharmaceutical solution (i.e. all of the solutionthat is not diverted for quality control testing) flows into the dosevessel 200, ready for administration to a patient.

Once the samples are in the sample vessels 402 a-e of the sample card40, an operator inserts the sample card 40 into the QCM 50, as is shownin FIG. 2. As shown in FIG. 4, the radiopharmaceutical samples travelfrom the sample vessels 402 a-e into the test vessels 502, 602, 702,802, and 902 within the QCM 50. Within the QCM 50, instruments exist toperform a number of automated quality control tests for each run ofradiopharmaceutical produced by the radiopharmaceutical synthesissystem.

To test for color and clarity, a light source 504 shines white lightthrough the sample in the test vessel 502. An electronic eye 506 thendetects the light that has passed through the sample and measures thatlight's intensity and color against reference samples.

To test the acidity of the radiopharmaceutical solution, pH test device604, i.e. a pH probe or pH colorstrip, measures the pH of the sample inthe sample vessel 602.

To test for the presence of volatile organics, a heat source 704 heatsthe sample in the test vessel 702 to approximately 150 degrees Celsiusso that the aqueous sample components, now is gas form, enter anadjacent gas chromatograph 706. A gas sensor microarray 708 (informally,an “electronic nose”) then detects the presence and prevalence (e.g. asppm) of such chemicals as methyl cyanide and ethanol.

To test for the presence of kryptofix, the sample in the test vessel 802is placed on a gel 804 comprising silica gel with iodoplatinate. Thesample and gel 804 are then warmed, and a color recognition sensor 806measures the resultant color of the sample, with a yellow colorindicating the presence of kryptofix.

To test the radiochemical purity of the sample, the sample in the testvessel 902 is eluted through a silica column 904 using a carrier mixtureof acetonitrile and water. In some embodiments, the acetonitrile andwater are mixed in a ratio of 9:1. A radiation probe 906 measures theactivity of the solution as it is eluted. As [¹⁸F]FDG has an elutiontime that can be predicted with accuracy, the probe 906 measures thepercentage of the activity that elutes at or very near to the predictedelution time for [¹⁸F]FDG. A percentage of 95% or higher indicatesacceptable radiochemical purity.

Additionally, a filter integrity test is also performed for every dosethat is produced. As shown in FIG. 3, after the radiopharmaceuticalsolution has gone through the filter 170, the integrity of the filter170 is tested by passing inert gas from the inert gas input 142 throughthe filter 170 at increasing pressure. A pressure sensor 302 measuresthe pressure of the inert gas upon the filter 170 and detects whetherthe filter 170 is still intact. The filter 170 should be capable ofmaintaining integrity under pressures of at least 50 pounds per squareinch (psi).

FIG. 5 displays a schematic view of one embodiment of the dose synthesiscard 30 a together with the attached sample card 40 a. The dosesynthesis card 30 a includes a reaction vessel 110 a where theradiopharmaceutical solution is synthesized, an additional line forautomatic extraction of QC sample 1600, and an RF ID chip or barcode1602 for radiopharmaceutical identification. The purpose of the RF IDchip or barcode 1602 is to uniquely identify the type ofradiopharmaceutical that is being produced so that a user does notmistakenly produce a radiopharmaceutical which is incompatible with thecard. A radioisotope input 112 a introduces the radioisotope F-18 intothe reaction vessel 110 a through a radioisotope input channel 1121. Atthis stage, the radioisotope is still mixed with quantities of heavywater from the biomarker generator. Next, an organic input 124 aintroduces a solution of potassium-kryptofix complex in acetonitrileinto the reaction vessel 110 a through an organic input channel 1241. Acombination nitrogen-input and vacuum 154 pumps nitrogen gas into thereaction vessel 110 a through a gas channel 1540 a and a valve 1541,which valve is at that time in an open position. The mixture in thereaction vessel 110 a is heated in nitrogen atmosphere to azeotropicallyremove water from the mixture, the vaporized water being evacuatedthrough the gas channel 1540 a and the vacuum 154. Next, the organicinput 124 a introduces mannose triflate in dry acetonitrile into thereaction vessel 110 a through the organic input channel 1241. Thesolution is heated at approximately 110 degrees Celsius forapproximately two minutes. By this stage, the F-18 has bonded to themannose to form the immediate precursor for [¹⁸F]FDG, FTAG. Next,aqueous hydrochloric acid is introduced into the reaction vessel 110 athrough an aqueous input 132 a and an aqueous channel 1321. Thehydrochloric acid removes the protective acetyl groups on theintermediate ¹⁸F-FTAG, leaving ¹⁸F-fludeoxyglucose (i.e. [¹⁸F]FDG). FIG.6 is an embodiment of the dose synthesis card with no sample card andonly a QC draw line 400. The necessity for a sample card is dependent onthe radiopharmaceutical used for production.

Having been synthesized, the [¹⁸F]FDG in solution passes from thereaction vessel 110 a through a post-reaction channel 1101 into a firstseparation column or purification component column 1601 a, where someundesirable substances are removed from the solution, thereby clarifyingthe radiopharmaceutical solution. In some embodiments, the purificationcomponent column 160 a comprises a solid phase extraction (SPE) having alength with an ion exchange resin, a length filled with alumina, and alength filled with carbon-18. The radiopharmaceutical passes through thefirst purification component column 1601 a and in some embodimentspasses through a second purification component 1601 b with a mobilephase that in many embodiments includes acetonitrile from the organicinput 124 a. The purification components 1601 a, 1601 b can be singlephase extraction components or trap-and-release purification componentsdepending on the radiopharmaceutical. As some of the mobile phase andimpurities emerge from the purification components 1601 a, 1601 b, theypass through a second post-reaction channel 1542 and through a three-wayvalve 175 and waste channel 1104 into a waste receptacle 210. As theclarified radiopharmaceutical solution emerges from the SPE column 160a, the radiopharmaceutical solution next passes through the secondpost-reaction channel 1542 and through the three-way valve 175 into afilter channel 1103 and then through a filter 170 a. The filter 170 aremoves other impurities (including particulate impurities), therebyfurther clarifying the radiopharmaceutical solution. In many embodimentsthe filter 170 a includes a Millipore filter with pores approximately0.22 micrometers in diameter.

Once the radiopharmaceutical solution has passed through the filter 170a, the clarified radiopharmaceutical solution travels via thepost-clarification channel 1105 into the sterile dose administrationvessel 200 a, which in the illustrated embodiment is incorporated into asyringe 202 or a collection vial. In some embodiments, the doseadministration vessel is filled beforehand with a mixture of phosphatebuffer and saline. As the clarified radiopharmaceutical solution fillsthe sterile dose administration vessel 200 a, some of the solution isdiverted through an extraction channel 1401, an open valve 1403, and atransfer channel 1402 into the sample card 40 a. The sample card 40 acontains a number of sample loops 404 a-h, which hold separated aliquotsof solution for imminent testing, and a number of valves 408 a-h, whichat this stage are closed. Once the test-sample aliquots ofradiopharmaceutical solution are collected, the sample card 40 a isseparated from the dose synthesis card 30 a and inserted into the QCM,as was shown in FIGS. 2 and 4. The aliquots then travel through thenow-open valves 408 a-h into the sample egress ports 406 a-h, from whichthe aliquots pass into the test vessels, as was shown in FIG. 4. In thesome embodiments, each of the sample loops 404 a-h holds approximately10 microliters of sample solution. The number of sample loops will varyaccording to the number of quality control tests to be performed forthat run, and the system is adapted to operate with different samplecards containing varying numbers of sample loops. After the samplealiquots pass into the sample card 40′, any excess solution remaining inthe dose administration vessel 200 a is extracted by a vent 156 througha first venting channel 1560 b and thence conveyed through an open valve1561 and through a second venting channel 1560 a into the wastereceptacle 210. The vacuum 154 evacuates residual solution from thetransfer channel 1402 through a now-open valve 1403 and a solutionevacuation channel 1540 b.

FIG. 6 is a schematic illustration of another example embodiment of thepresent general inventive concept, illustrating dose synthesis card 30 bwithout a sample card. FIG. 7 shows the same example embodiment,illustrating the QC draw line 1600 connecting the dose synthesis card 30b to the QCM 51.

In some embodiments of the present invention, the CPM 20 holdssufficient amounts of reagents and solvents that are required during theradiopharmaceutical synthesis process to carry out multiple runs withoutreloading. Indeed, in some embodiments the CPM 20 is loaded withreagents and solvents approximately once per month, with that month'ssupply of reagents and solvents sufficient to produce several dozen oreven several hundred doses of radiopharmaceutical. As the reagents andsolvents are stored in the CPM 20, it is easier than under previoussystems to keep the reagents and solvents sterile and uncontaminated. Insome embodiments, a sterile environment is supported and contaminationinhibited by discarding each dose synthesis card 30 and the sample card40 after one run; these components of the system are adapted to bedisposable.

Thus, each batch of reagents and solvents, loaded periodically into theCPM 20, will supply a batch of multiple doses of radiopharmaceutical,each dose produced in a separate run. Some quality control tests areperformed for every dose that is produced, while other quality controltests are performed for every batch of doses. For example, in oneembodiment of the present invention, the filter integrity test, thecolor and clarity test, the acidity test, the volatile organics test,the chemical purity test, and the radiochemical purity test areperformed for every dose. On the other hand, some quality control testsneed be performed only once or twice per batch, such as the radionuclidepurity test (using a radiation probe to measure the half-life of theF-18 in the [¹⁸F]FDG), the bacterial endotoxin test, and the sterilitytest. These tests are performed generally on the first and last doses ofeach batch. Because these per-batch quality control tests are conductedless frequently, they may not be included in the QCM, but rather may beconducted by technicians using separate laboratory equipment.

While the present invention has been illustrated by description of oneembodiment, and while the illustrative embodiment has been described indetail, it is not the intention of the applicant to restrict or in anyway limit the scope of the appended claims to such detail. Additionalmodifications will readily appear to those skilled in the art. Theinvention in its broader aspects is therefore not limited to thespecific details, representative apparatus and methods, and illustrativeexamples shown and described. Accordingly, departures may be made fromsuch details without departing from the spirit or scope of applicant'sgeneral inventive concept.

What is claimed is:
 1. A disposable microfluidic radiopharmaceuticalsynthesis card system comprising: at least one reaction vessel adaptedto receive a radioisotope and at least one reagent, said reaction vesselbeing configured to receive energy from an energy source inenergy-transfer communication with an energy source, whereby when saidradioisotope and said at least one reagent are mixed in said reactionvessel and energy is provided to said reaction vessel from said energysource, a radiopharmaceutical solution is synthesized; at least onepurification component to purify said radiopharmaceutical solution; afilter adapted to sterilize said radiopharmaceutical solution; a sterilesyringe adapted to receive sterile radiopharmaceutical solutionfollowing the passage of said radiopharmaceutical solution through saidpurification column and said filter; and a port in said syringe used toextract a sample of said radiopharmaceutical solution for qualitycontrol testing; wherein said reaction vessel, said purificationcomponent, said port, and said filter are incorporated into a disposablecard, said card being discardable after one (1) run.
 2. The system ofclaim 1 further comprising a sample card adapted to receive multiplealiquots of said purified radiopharmaceutical solution for testingfollowing said purified radiopharmaceutical solution's passage throughsaid purification column.
 3. The system of claim 1 wherein at least oneof said at least one purification component is selected from the groupconsisting of trap and release, and solid phase extraction.
 4. Thesystem of claim 1 wherein at least one of said reagents is located onthe card.
 5. The system of claim 1 wherein said radioisotope is selectedfrom the group consisting of carbon-11, nitrogen-13, oxygen-15,fluorine-18, iodine-124, and gallium-68.
 6. The system of claim 1wherein said radiopharmaceutical is selected from the group consistingof [18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride, [18F]3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole, [18F]flurocholine,[18F]Fallypride, [18F]Florbetaben, [18F]Florbetapir,[18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]FDOPA,[11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone,[11C]Carfentanil and [11C]Raclopride.
 7. A disposable microfluidicradiopharmaceutical synthesis card comprising: at least one reactionvessel adapted to receive a radioisotope and at least one reagent, saidreaction vessel being in energy-transfer communication with an energysource, whereby when said radioisotope and said at least one reagent aremixed in said reaction vessel and energy is provided to said reactionvessel from said energy source, a radiopharmaceutical solution issynthesized; at least one purification component used to purify saidradiopharmaceutical solution; a port used to extract a sample of saidradiopharmaceutical solution for quality control testing; a filteradapted to sterilize said radiopharmaceutical solution; and a sterilesyringe to receive sterile radiopharmaceutical solution following thepassage of said radiopharmaceutical solution through said purificationcolumn and said filter.
 8. The card of claim 7 wherein at least one ofsaid at least one purification component is selected from the groupconsisting of trap and release, and solid phase extraction.
 9. The cardof claim 7 wherein at least one of said reagents is located on the card.10. The card of claim 7 wherein said radioisotope is selected from thegroup consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18,iodine-124, and gallium-68.
 11. The card of claim 7 wherein saidradiopharmaceutical is selected from the group consisting of[18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride, [18F]3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole, [18F]flurocholine,[18F]Fallypride, [18F]Florbetaben, [18F]Florbetapir,[18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]FDOPA,[11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone,[11C]Carfentanil and [11C]Raclopride.